DALLAS – The suspected link between azithromycin and an increased incidence of cardiovascular events was borne out in a recent VA study of veterans hospitalized with pneumonia, but that was only part of the story: The treatment regimen including azithromycin also lowered the patients’ overall risk of dying.

“Our conclusion is that, for older patients hospitalized with pneumonia, azithromycin therapy is a safe and beneficial treatment for these patients, that for every one nonfatal myocardial infarction we prevent seven deaths by using this therapy,” explained lead author Eric M. Mortensen, MD, MSc, of the VA North Texas Health Care System and the University of Texas Southwestern Medical Center, both in Dallas.

Results of the study, which looked at 65,000 older patients treated at VA hospitals during a decade ending in 2012, were published recently in the Journal of the American Medical Association.1

Click the graphic to expand to full-size in a new tab

The researchers said they embarked on the study because clinical practice guidelines call for the use of azithromycin and other macrolides as first-line therapies for inpatients with pneumonia. Some recent research, however, has raised alarms about the antibiotics’ risk for increasing cardiovascular events, according to the article’s background.

For example, University of South Carolina researchers reported in March that, in terms of avoiding potentially fatal heart rhythms, amoxicillin appeared to be a safer antibiotic choice than either azithromycin or levofloxacin. 2

That study was conducted in response to a 2013 warning from the Food and Drug Administration on azithromycin use and the risk of potential fatal heart rhythms. The FDA, in turn, had cited a New England Journal of Medicine article in 2012 on a study comparing the risks of cardiovascular death in patients treated with the antibacterial drugs azithromycin, amoxicillin, ciprofloxacin and levofloxacin, or no antibacterial drug. The study reported an increase in cardiovascular deaths. In the risk of death from any cause, in persons treated with a five-day course of azithromycin compared with all of the other intervention groups except levofloxacin, which had similar results to those associated with azithromycin treatment.

Publicizing their concerns, FDA officials conceded, however, “the potential risk of QT prolongation with azithromycin should be placed in appropriate context when choosing an antibacterial drug: Alternative drugs in the macrolide class, or non-macrolides such as the fluoroquinolones, also have the potential for QT prolongation or other significant side effects that should be considered when choosing an antibacterial drug.”3

The objective of the recent research, Mortensen explained in an interview made available by JAMA, “was to examine both the safety and the harm potentially associated with azithromycin therapy for elderly patients hospitalized with pneumonia in the VA healthcare system.”

For the study, the cases of 31,863 patients who received azithromycin were compared to another 31,863 patients with similar characteristics who received another guideline-recommended therapy.

Overall, 90-day mortality was found to be significantly lower in those who received azithromycin — 17.4% vs. 22.3%, but odds of having a heart attack were higher — 5.1% vs 4.4%. Similar elevated risk was not seen for other cardiac events, 43.0% vs. 42.7%; cardiac arrhythmias 25.8% vs. 26.0%; or heart failure 26.3% vs. 26.2 %.

“In this national cohort study of veterans hospitalized with pneumonia, azithromycin use was consistently associated with decreased mortality and a slightly increased odds of myocardial infarction,” the authors write. “To put the balance of benefits and harms in context, based on the propensity-matched analysis, the number needed to treat with azithromycin was 21 to prevent one death within 90 days, compared with a number needed to harm of 144 for myocardial infarction. This corresponds to a net benefit of around seven deaths averted for one nonfatal myocardial infarction induced.”

The researchers speculated on why that would be the case.

“This study’s results raise the question: Why would azithromycin be associated with a mild increased odds of cardiac events but decreased odds of mortality?”, they asked. “The beneficial effects of azithromycin, and of macrolides in general, as compared with other guideline-concordant antibiotic regimens for pneumonia may be due less to their antimicrobial propensities but more to their effect on immune function. Previous studies have demonstrated that macrolides have significant anti-inflammatory effects.”

Mortensen called for randomized clinical trials to confirm the study’s findings and suggested that future research could address why “many patients do not receive azirothymcin therapy when they are hospitalized with pneumonia.”